PT  - JOURNAL ARTICLE
AU  - Liangliang Cai
AU  - Hua Bai
AU  - Jianchun Duan
AU  - Zhijie Wang
AU  - Shugeng Gao
AU  - Di Wang
AU  - Shuhang Wang
AU  - Jun Jiang
AU  - Jiefei Han
AU  - Yanhua Tian
AU  - Xue Zhang
AU  - Hao Ye
AU  - Minghui Li
AU  - Bingding Huang
AU  - Jie He
AU  - Jie Wang
TI  - Epigenetic alterations are associated with tumor mutation burden in non-small cell lung cancer
AID  - 10.1186/s40425-019-0660-7
DP  - 2019 Dec 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - 198
VI  - 7
IP  - 1
4099  - http://jitc.bmj.com/content/7/1/198.short
4100  - http://jitc.bmj.com/content/7/1/198.full
SO  - J Immunother Cancer2019 Dec 01; 7
AB  - Background To profile genomic and epigenomic of a naïve Chinese non-small cell lung cancer (NSCLC) cohort and investigate the association between tumor mutation burden (TMB) and DNA methylation (DNAm) to explore potential alternative/complimentary biomarkers for NSCLC immunotherapies.Methods A total of 89 tumor tissues with matched normal tissues from Chinese NSCLC patients were collected and subjected to whole exome sequencing (WES). From comparison, each patient was evaluated for the TMB value and divided into high, medium and low TMB based on TMB tertile distribution and then relatively high and low TMB samples were selected and subjected to DNAm profiling.Results Patients in the low (n = 30), medium (n = 29), and high (n = 30) TMB tertiles had 1.1–2.5, 2.5–4.1, and 4.2–13.9 mutations/Mb, respectively. A statistical directly association between differential methylation probes (DMPs) and TMB level was observed in our cohort (r = 0.63, P value =0.0003) and this was confirmed by using TCGA NSCLC dataset (r = 0.43, P value =0.006). Relatively high TMB group (n = 16, 7.5–13.9 mutations/Mb) harbors more differential DMPs while less in relatively low TMB group (n = 13, 1.1–2.4 mutations/Mb). Eight hundred fifty-eight differential methylation regions (DMRs) were found in relatively high TMB group. In addition, 437 genes show DNAm aberrance status in high TMB patient group and 99 have been reported as its association with lung cancer.Conclusion To our knowledge, this is the first report for direct link between the methylome alterations and TMB in NSCLCs. High TMB NSCLCs had more DNAm aberrance and copy number variations (CNVs). In addition, the TMB distribution of Chinese NSCLCs population is lower than that of TCGA.Liangliang Cai and Hua Bai contributed equally to this work.Abbreviations:BHBenjamini-HochbergCD4TCluster of differentiation 4 positive T cellCD8TCluster of differentiation 8 positive T cellCNVCopy number variationCTLA4Cytotoxic T-lymphocyte–associated antigen 4DMPDifferential methylation probeDMRDifferential methylation regionDNAmDNA methylationEGFREpidermal growth factor receptorFDRFalse discovery rateGOGene ontologyHOXHomoeoboxINDELInsertion/deletion polymorphismJak-STATJanus kinase/signal transducers and activators of transcriptionLUADLung AdenocarcinomaLUSCLung Squamous Cell CarcinomaMVPMethylation variable positionNKNatural killer cellNOMNumber of mutationNSCLCNone small cell lung cancer;PCRPolymerase chain reactionPD-1Programmed cell death protein 1PD-L1Programmed death-ligand 1SCNAsomatic copy-number alterationSNVSingle nucleotide variationTMBtumor mutation burdenTP53Tumor protein p53TSSTranscription start siteWESWhole exome sequencing